Dopamine D2 Receptor Isoform Heteroreceptor Complexes with the Growth Hormone Secretagogue Receptor 1a Reveals Isoform-Specific Interaction Interface Dynamics

The dopamine D2 receptor (D2R), a class A G-protein-coupled receptor expressed in two isoforms at the central nervous system, has been implicated in several neuropsychiatric and neurodegenerative disorders. Although conventionally understood as a monomer, D2R can exist as homo- and heteroreceptor complexes, with each structural state conferring distinct functional properties. The heteromer formed by the D2R and the growth hormone secretagogue receptor (GHSR1a) has been primarily studied in the context of eating disorders, but more recently, in Parkinson’s disease mouse models. Besides the neuropharmacological relevance of this heteromer, the molecular mechanisms underlying their interaction interface in complex formation have not been fully understood. Moreover, the specific contribution of each D2R isoform to both the formation and functional properties of the D2R/GHSR1a heteroreceptor complex remains to be elucidated. Therefore, in this study, we aimed to characterize the structural and dynamic differences between D2R short and long isoforms, both as monomers and within the D2R/GHSR1a heterocomplexes. Through computational methodologies including homology modeling, receptor–receptor docking, and coarse-grained molecular dynamic simulations, we observed distinct behaviors for D2R isoforms as monomers and in heteromeric assemblies with GHSR1a. Our findings showed differences in D2R isoform motions that may impact their activation along with isoform-specific interaction interfaces with GHSR1a. Furthermore, these differential interfaces promoted site-to-site and ligand-binding pocket differences for both D2R isoforms, suggesting isoform-specific allosteric regulation potentially mediated by GHSR1a within the D2R/GHSR1a heterocomplexes. Overall, our results highlight the isoform-dependent mechanisms within the D2R/GHSR1a heteromer that influence complex formation, ligand binding, and intracellular signaling, providing a framework for future therapeutic strategies targeting D2R/GHSR1a heteroreceptor complexes.